Melanoma is an aggressive form of skin cancer that has recently undergone an alarming increase in incidence. Although cures can be achieved with surgical resection of localized lesions, the advanced stages of melanoma are only poorly responsive to currently approved therapies. The 5-year survival rate for stage IV metastatic melanoma is approximately 10%. New therapeutic approaches, including antisense to Bcl2, antibodies to CTLA4, small molecule RAF kinase inhibitors, and adoptive immunotherapy, are currently in clinical testing for metastatic melanoma. The results from some of these recent studies seem to be encouraging, but a durable impact on overall survival will likely require therapeutic combinations including additional new agents.
More than 20 years ago, endothelin-1 (ET-1) was isolated from aortic endothelial cells and found to have potent vasoconstrictive activity. The receptors for endothelins were cloned shortly thereafter and their expression in various cell types, including melanocytes and melanoma cells, pointed to functions independent of their role in endothelium. It is now well recognized that the endothelin B receptor (ETBR, EDNBR) is critical for the faithful derivation of melanocytic cells emanating from the neural crest during embryonic development. Melanocyte precursors rely on ETBR activity to proliferate and migrate from the neural tube to their final destinations. Mice with defective genes coding for either ETBR or endothelin-3 (ET-3) exhibit a pigmentation deficit in their coats and a shortage of enteric ganglion cells, also derived from the neural crest. These characteristics strongly resemble those associated with the WS4 variant of Waardenburg syndrome in humans, which has been attributed to germline mutations in either ET-3 or ETBR. An additional variant of this syndrome, WS2, has been mapped to heritable mutations in the microphthalmia-associated transcription factor (MITF), a key regulator of melanocyte development and a melanoma proto-oncogene.
The strong genetic evidence linking ETBR activity to the fate of melanoblasts underscores a potential role for this receptor in the progression of melanoma. The expression of ETBR mRNA and protein was reported to increase during disease progression from dysplastic nevi to metastatic melanoma. Blockade of ETBR activity by 2 independent small molecule inhibitors interfered with growth and survival of melanoma cells and tumor xenografts. These preclinical studies implicate ETBR as a potential driver of melanoma progression.
There is a need in the art for agents that target ETBR for the diagnosis and treatment of ETBR-associated conditions, such as cancer. The invention fulfills that need and provides other benefits.